The microRNA-9/B-lymphocyte-induced maturation protein-1/IL-2 axis is differentially regulated in progressive HIV infection

Authors

  • Nabila Seddiki,

    Corresponding author
    1. St Vincent's Centre for Applied Medical Research, Darlinghurst, NSW, Australia
    2. National Centre in HIV Epidemiology and Clinical Research, University of NSW, Kensington, NSW, Australia
    Current affiliation:
    1. The Vaccine Research Institute (VRI), Université Paris-Est Créteil, INSERM U955 équipe 16, Faculté de Médecine, Créteil, France
    • Full correspondence: Dr. Nabila Seddiki, INSERM U955, Equipe 16, Faculté de Médecine Henri Mondor, 8 rue du Général Sarrail, 94010 Créteil Cedex, France

      Fax: +33-1-49-81-37-09

      e-mail: nabila.seddiki@inserm.fr

      See accompanying Commentary by Thaventhiran and Fearon

    Search for more papers by this author
  • Chansavath Phetsouphanh,

    1. St Vincent's Centre for Applied Medical Research, Darlinghurst, NSW, Australia
    2. National Centre in HIV Epidemiology and Clinical Research, University of NSW, Kensington, NSW, Australia
    Search for more papers by this author
    • These authors contributed equally to this work.

  • Sanjay Swaminathan,

    1. St Vincent's Centre for Applied Medical Research, Darlinghurst, NSW, Australia
    2. National Centre in HIV Epidemiology and Clinical Research, University of NSW, Kensington, NSW, Australia
    Search for more papers by this author
    • These authors contributed equally to this work.

  • Yin Xu,

    1. St Vincent's Centre for Applied Medical Research, Darlinghurst, NSW, Australia
    2. National Centre in HIV Epidemiology and Clinical Research, University of NSW, Kensington, NSW, Australia
    Search for more papers by this author
  • Sudha Rao,

    1. The John Curtin School of Medical Research, Australian National University, Canberra City, ACT, Australia
    Search for more papers by this author
  • Jasmine Li,

    1. The John Curtin School of Medical Research, Australian National University, Canberra City, ACT, Australia
    Search for more papers by this author
  • Elissa L. Sutcliffe,

    1. The John Curtin School of Medical Research, Australian National University, Canberra City, ACT, Australia
    Search for more papers by this author
  • Gareth Denyer,

    1. Biochemistry, School of Molecular Bioscience, The University of Sydney, Sydney, NSW, Australia
    Search for more papers by this author
  • Robert Finlayson,

    1. Taylor Square Clinic, Darlinghurst, NSW, Australia
    Search for more papers by this author
  • Linda Gelgor,

    1. St Vincent's Centre for Applied Medical Research, Darlinghurst, NSW, Australia
    2. National Centre in HIV Epidemiology and Clinical Research, University of NSW, Kensington, NSW, Australia
    Search for more papers by this author
  • David A. Cooper,

    1. St Vincent's Centre for Applied Medical Research, Darlinghurst, NSW, Australia
    2. National Centre in HIV Epidemiology and Clinical Research, University of NSW, Kensington, NSW, Australia
    Search for more papers by this author
  • John Zaunders,

    1. St Vincent's Centre for Applied Medical Research, Darlinghurst, NSW, Australia
    Search for more papers by this author
  • Anthony D. Kelleher

    1. St Vincent's Centre for Applied Medical Research, Darlinghurst, NSW, Australia
    2. National Centre in HIV Epidemiology and Clinical Research, University of NSW, Kensington, NSW, Australia
    Search for more papers by this author

Abstract

The fine control of T-cell differentiation and its impact on HIV disease states is poorly understood. In this study, we demonstrate that B-lymphocyte-induced maturation protein-1 (Blimp-1/Prdm1) is highly expressed in CD4+ T cells from chronically HIV-infected (CHI) patients compared to cells from long-term nonprogressors or healthy controls. Stimulation through the T-cell receptor in the presence ofIL-2 induces Blimp-1 protein expression. We show here that Blimp-1 levels are translationally regulated by microRNA-9 (miR-9). Overexpression of miR-9 induces Blimp-1 repression, restoring IL-2 secretion in CD4+ T cells via reduction in the binding of Blimp-1 to the il-2 promoter. In CHI patients where IL-2 expression is reduced and there is generalized T-cell dysfunction, we show differential expression of both miR-9 and Blimp-1 in CD4+ cells compared with levels in long-term nonprogressors. These data identify a novel miR-9/Blimp-1/IL-2 axis that is dysregulated in progressive HIV infection.

Ancillary